Production of tertiary amines from nitrogen compounds



' catalyst.

Patented 6, 1945 T OFFICE PRODUCTION OF TERTIARY AMINES FROM NITROGEN-COMPOUNDS William S. Emerson, Dayton, Ohio No Drawing. Originalapplication December 16 1940, Serial No. 370,355.

Divided and this application September 15, 1944, Serial No. 554,330

8 Claims.

The present invention relates to the reductive alkylation of amines,nitro, nitroso and azo compounds by means of aldehydes or ketones andhydrogen gas in the presence of a hydrogenation The invention relatesparticularly to alkylation inthe nitrogen-containing radical of theamino, nitro, nitroso or azo compound to produce N-alkyl or N-aralkylsubstituted amines. The invention also relates to methods of controlling the proportion of secondary and tertiary amines produced in suchreactions and is specifically directed to the production secondary andtertiary amines.

The principal objects of the present invention are to provide a simpleand economical method of obtaining N-alkylated of N-araylkylated aminesby the reduction with hydrogen of an aldehyde or a ketone and an amine,nitro, nitroso. or azo compound or an intermediate condensation productof the specified carbonyl compounds and one of the nitrogen compounds.Another object of the invention is to provide a method of such reductivealkylation of nitrogen compounds whereby the yield of secondaryN-monoalkylated or tertiary N-dialkylated amines may be controlled tothe extent of suppressing or entirely eliminating the formation of theundesired alkylated amines. Other objects and advantages of theinvention, some of which are specifically referred to hereinafter, willbe apparent to those skilled in the art.

This application is a division of my copending application S. N.370,355, filed December 16, 1940. In my application S. N. 332,975, filedMay 2, 1940 now issued as U.,S. Patent 2298,284, of which my copendingapplication S. N. 370,355, filed December 16. 1940, is acontinuation-in-part. I have disclosed that by reducing a mixture of anaidehyde and a nitro or amino compound with hydrogen in the presence ofa platinum or Raney nickel reduction catalyst under neutral or sli htlyalkaline reaction conditions, secondary amines are formed while thesimultaneous formation of tertiary amines is suppressed or entirelyavoided.

Such neutral or slightly basic or alkaline conditions are obtained byplacing in the reaction mixture undergoing hydrogenation an alkali-metalsalt of a weak organic acid such as sodium acetate, sodium carbonate,sodium stearate or the like. I have also shown in my copendingapplication Serial No. 370.355 and in my application Serial No. 332,975,that if acid conditions are maintained in a similar reaction mixture,for example, by the presence of trimethylamine hydrochloride in thereaction mixture, tertiary amines are formed to the exclusion orsuppression of secondary amines.

I have discovered that in such reductive alkylations with nitrogencompounds and carbonyl compounds, neutral or slightly basic reactionconditions maintained by the addition of sodium acetate or otheralkali-metal salts of weak organic acids favor the formation ofsecondary amines while acid conditions maintained by the addition oftrimethylamine hydrochloride, acetic acid or the like, favo theformation of tertiary amines.

Although I refer to neutral or basic and acid conditions or mediathroughout this specification, it is not to be understood that acidityor alkalinity in and of itself is directly responsible for theimprovements specified. Sodium acetate, acetic acid or trimethylaminehydrochloride do change the pH or hydrogen-ion concentration of thereaction mixture, but they probably act by virtue of their ability tofavor certain condensation reactions or the like rather than as a resultof their acidity. Sodium hydroxide, for example, which produces alkalinemedia, hinders reaction. Hence it is to be understood that when acid orbasic media or conditions are referred to, these terms are used merelyfor convenience to classify the various kinds of condensing agents whichare added to the reaction mixture,

When the carbonyl compound used in such reactions is a ketone instead ofan aldehyde, somewhat more drastic reaction conditions, such as highertemperatures, are necessary to produce secondary amines in neutral orslightly basic media. Ketones do not yield tertiary amines in neutral orslightly basic media. In acid media, on the other hand, ketones yieldsecondary instead of tertiary amines, even under drastic reactionconditions such as elevated temperatures of reaction and concentratedacid;

I have also discovered that besides amines and nitro compounds, othernitrogen compounds such as nitroso and azo compounds, for example,nitrosobenzene and azobenzene, may be used in the reactions.Furthermore, I have found that substituents such as hydroxyl and aminoradicals in the nitrogen compound have an activating effect on thereaction. Thus, when an aromatic nitrogen compound contains an amino ora hydroxyl group ortho, or particularly, para, to the nitro, amino,nitroso or azo group, the reductive alkylation of such substitutedcompound with ketones progresses more rapidly to the formation ofsecondary amines while with aldehydes, reaction is also accelerated andtertiary amines are formed in either basic or acid media. Alkyl groupssubstituted in the benrene ring also have a mild activating influencewhich is less pronounced than that of amino or hydroxyl groups, however.In the case of azo compounds, hydroxy or dimethylamine groups, eitherortho or para to the azo group, have an activating influence andtertiary amines are formed in alkaline or acid media.

The methods of adopting the present discoveries and those of mycopending application, S. N. 370,- 355, and my application, S. N.332,975, to the production of secondary or tertiary amines by reductivealkylation are set forth in the examples which follow hereinafter, butmay be briefly summarized as follows:

A. Secondary amines may be made by the reaction of hydrogen in thepresence of a hydrogenation catalyst on a reaction mixture comprising:

3. An unsubstituted nitrogen compound or a. nitrogen compound free fromactivat-.

ing substituents, as in 1, together with a ketone in an acid medium orin an alkaline medium under more drastic reaction conditions.

B. Tertiary amines may be made by the reaction" of hydrogen in thepresence of a hydrogenation catalyst on a reaction mixture comprising:

1. A nitrogen compound (nitro, amino, ni-- troso or azo compound), withor without activating substituents, together with an aldehyde in acidmedia, or

2. A secondary amine together with an aldehyde in an acid medium.

Ketones are inactive or are not as reactive as aldehydes in theformation of tertiary amines, either in acid or alkaline media, evenunder drastic reaction conditions. They may be advantageously used,however, in the production of secondary amines in accordange with theprocesses summarized above, especially when used in an acid instead ofan alkaline medium. The reaction or primary aromatic amines withaldehydes, particularly formaldehyde, in acid media, is complicated bythe formation of tarry condensation products of the type ofanhydroformaldehyde-aniline and the like and hence, to avoid suchformation of condensation products, resort should be made to primaryaromatic nitro compounds or the like as starting materials;suchcondensation products do not readily form between primary aromaticamines and ketones or secondary aromatic amines and either aldehydes orketones and hence reaction mixtures containing these compounds may beused. When formaldehyde is used in any re-' action mixture under acidconditions comp tions are also likely to result from polymerization ofthe formaldehyde. These complications do not asaacov result withacetaldehyde or higher aldehydes when used in the acid reaction mixturescontemplated by the present invention, however. The reductive alkylationproduct of formaldehyde and primary aromatic amines, furthermore, is atertiary amine, in many cases, even in alkaline reaction media.

The yields in the foregoing alternative processes for the production ofsecondary or tertiary amines vary somewhat and hence one will bepreferable to another. The processesalso difler in the propor tion ofsecondary or tertiary amines which are formed. By using ketones toprepare secondary amines, for example, it is possible to operate in sucha manner that no substantial proportion of tertiary amine is formed as aby-product, which may be highly desirable, whereas in a reaction wherethe tertiary amine is the desired product it may be more economical toadopt an alternative which gives a high yield of tertiary amine that maybe contaminated with small proportions of secondary amines in preferenceto one which gives a small yield of tertiary amine uncontaminated withsecondary amines, since secondary amines can be converted in a separatesubsequent step to tertiary amines.

It is known that secondary and tertiary amines have been prepared byreductive alkylation by the use of nascent hydrogen generated in situfrom the reaction of a metal and an acid or by the use of hydrogen gasin the presence of a nickel catalyst at high temperatures to 200 C.) andunder high pressures (50 to 150 atmospheres). That such reactions couldbe conducted with hydrogen gas in the presence of a hydrogenationcatalyst under relatively mild reaction conditions (room temperature andpressures of about 2 to 4 atmospheres) by the use of the specified acidsor salts which modify the acidity (pH or hydrogenion concentration) ofthe reaction medium and serve as condensing agents or modify thereaction in some other manner, was unexpected.

By means of the processes of the invention it has been possible toprepare in an advantageous manner amines which have not been heretoforeprepared or which could not be prepared by heretofore lmown methods.Since the methods disclosed herein show how alkylation may be stopped atthe formation of the secondary amine the methods are useful for thepreparation of tertiary amines having two different alkyl substituentson the amino nitrogen atom in an advantageous manner.

In the examples which follow, typical methods of practicing the processof my invention are set forth:

Example I.N-ethylaniline using acetaldehyde and alkaline conditions Intoan apparatus for catalytic reduction, preferably provided with a stirreror means for shaking, are placed 93 grams (about 1 mol) of anilinedissolved in 1500 cc. of 95% ethyl alcohol and about 88 grams (about 2mols) of acetaldehyde, 10 to 20 grams of fused sodium acetate, and about30 grams of Raney nickel catalyst, which may be prepared by the methodof Covert and Adkins described in the Journal of the American ChemicalSociety, 1932, vol. 54, page 4116. Other methods of preparing Raneynickel catalysts are described in U. S. Patents 1,563,587; 1,628,190;1,915,473; and 2,139,602. The apparatus is evacuated and then an initialpressure of about 3 atmospheres (45 lbs. per square inch) of hydrogen isapplied. The apparatus is maintain d at room temperature and thehydrogen is maintained at a pressure of about 3 atmospheres duringabsorption thereof. After hydrogen is no longer absorbed, which may beafter an hour or more depending upon the rate of absorption, thereduction is stopped and the" catalyst is removed by filtration. Thesolution is acidified slightly and the alcohol is distilled off. Theremaining oil is then made slightly alkaline and fractionated, undervacuum if desired. N-ethylaniline has a distilling point of 204 C. Theyield is about 58% of the theoretical, based on the aniline used.

Example II.-N-n-heptylaniline using heptaldehi/de and alkalineconditions By proceeding as in Example I, using from 2 to 5 mols ofheptaldehyde instead of acetaldehyde and fractionating the product invacuum, N-n heptylaniline is obtained.

N-n-heptylaniline has a boiling point of to C. at a pressure of 30 mm.,a specific gravity of 0.906 at 20/20 C. and a refractive index at 20 C.of 1.5080 for the sodium D line.

Ezamfle-IIL-N-n-hutirl alpha naphthylamine using bntyraldehyde andalkaline conditions By proceeding as in Example I but substitutingbutyraldehyde for acetaldehyde and alpha-naphthylamine for aniline inmolecular proportions,

and fractionating the product in vacuum, N-nbutyl-alpha-naphthylamine isobtained in 80% of the theoretical yield.

The new compound, N-n-butyl-alpha-naphthylamine, has a boiling point of155 to 167 C. at a pressure of 8 mm., a specific gravity of 1.004 at20/20 and a'refractive index of 1.5963 at 20 C. for the sodium D line.Its hydrochloride melts at 151 to 152 C.

Example IV.-N-ethyl-p-anisidine using acetaldehude and alkalineconditions By proceeding as in Example I but substituting p-anisidinefor aniline in molecular proportionsv and fractionating the product,N-ethyl-p-anisidine is obtained in 51% yield.

N-ethyl-p-anisidine has a boiling point of to C. at a pressure of 20mm., a specific gravity of 1.017 at 20/20 and a refractive index of1.5444 at 20 C. for the sodium D line. Its para-bromobenzenesuli'onamidemelts at 113 to 114 C.

Example V.--N-n-butul-p-anisidine using butulraldehyde and alkalineconditions Example VI.N-n-butylaniline from nitrobenacne andbutvraldehzide under alkaline conditions Into an autoclave provided witha stirrer are placed 123 grams (about 1 mol) of freshly distillednitrobenzene, 20 grams of fused sodium acetate, 1500 cc. of 95% ethylalcohol, 94 grams (about 1.3 mol) of freshly distilled n-butyraldehydeand 30 grams of Raney nickel catalysts. The autoclave is evacuated andthereafter an initial pressiire of 3 atmospheres of hydrogen is appliedto the autoclave and the mixture is maintained at room temperature.After about 4 mols of hydrogen have been absorbed, the reduction isstopped and the catalyst is removed by filtration or decantation. Thefiltrate is made slightly acid with hydrochloric acid and the alcohol isdistilled off. The residue is then diluted with about 1000 cc. of waterand made slightly alkaline with sodium hydroxide. It may be subsequentlyextracted with ether and the extracts combined and after evaporation ofthe ether, fractionally distilled. However, the original residue withoutdilution with water may be made basic and then subjected to vacuumdistillation. The product, N-n-butylaniline, is obtained in a yield ofabout 77% to 81% of the theoretical and has a boiling point of 235 to245 C.

Example VII.--N di n butzll p aminophenol from p-nitrophenol andbuturaldehyde under alkaline conditions I When p-nitrophenol issubstituted in Example VI for nitrobenzene and butyraldehyde is present.

in excess, the product obtained is substantially allN-di-n-butyl-p-aminophenol. It is difllcult to get any yield ofsecondary amine in this reaction because of the presence of theactivating hydroxyl group in the para position.

Ell-ample VIII.-p Chloro n butylaniline from p-chloronitrobenzene andbatz/raldehgde under alkaline conditions tained when nitrobenzene isreacted under the same conditions. The lack of activating influence ofthe chlorine is shown more than anything else by the presence ofunalkylated p-chloroaniline in the reaction mixture.

Example IX.--N-di-n-heptz l-p-toluidine from pnitrotoluene andheptaldehyde under alkaline conditions By substituting heptaldehyde forbutyraldehyde and p-nitrotoluene for nitrobenzene in molecularproportions in Example VI and proceeding as therein otherwise described,N-mono-n-heptyl-ptoluidine and N-di-n-heptyl-p-toluidine are obtained,the latter in a. yield of 34% of the theoretical. The latter compound,N-di-n-heptyl-ptoluidine, is a new compound and has a boiling point ofto 200 C. at a pressure of 2.5 mm., a specific gravity of 0.943 at 20/20and a refractive index of 1.5089 at 20 C. for the sodium D line. Itshydrochloride melts at 136 C. The methyl group of the nitrotoluene has amild activating influence, the formation of both secondary and tertiaryamines being a result thereof.

Example X.-N-ethylaniline using acetaldehydealkaline conditions andplatinum catalyst theses," coll. vol. I, 1932, page 452) for the Raneynickel catalyst and proceeding otherwise as in Example I, N-ethylanilineis obtained in a yield of 41% of the theoretical.

asaasov The product was further identified by means of its picrate,which had a melting point of 123 to 125' C. The melting point of theplcrate is given as 125 C. by Reilly and Hickinbottom, J. Chem.

Soc. 1 n on, 1918, 01.113, 9. Example XI.-N benzyl alpha naphthylamine 0Lo d v page 9 using benzaldehz de and alkaline conditions ExampleXIIL-N-n-di-n-butylaniline using niben cond ions By substitutingbenzaldehyde for acetaldehyde tm acne and acid it and alphanaphthylaminefor aniline in molecular By using 3 grams or Raney nickel catalystinproportions in Example I and proceeding as stead of the platinumcatalyst in Example XII otherwise therein indicated,benzyl-alpha-naphand 2 grams of trimethylamine hydrochloride thylamineis obtained. Its benzamide has a meltinstead oi the acetic acid, andusing 36.0 grams ing point of 103 to 104 C. (0.3 mol) of nitrobenzene,so that the ratio oi nitrobenzen t bu ralde de is 1:1, a d 1 TableI.Reductive alkylation of nitrobenzene 1s 63 i M N di n utylanil e isobtained. (The yield with butl'mldehyde media of d is 98% based on thealdehyde consumed.)

The eflect of various oi the added agents and The use F aldehyde thisacidity engendered by their use, as well as the preparation result inYield h influence of other factors, is illustrated in the amineiollowingresults. In these tests, the specified Example XIV Tema r1 amines usingnitro comquantity oi butyraldehyde was reacted with 0.10 pounds) acidcondition, and platinum catalyst, mol of nitrobenzene in the presence 013 grams of Raney nickel catalyst. The pH represents the I Adopting themethod of Example XII, using acidity of the reaction mixture as observedon a. glacial acetic acid to provide the acid medium Hellige pH meter.The yields are expressed as and platinum catalyst and substituting theapper cent of secondary (N-n-butylaniline) and proprlate aldehyde andnitro compound, the foltertiary amines (N-di-n-butylaniline)respeclowing yields of the respective aliphatic and arotively, matictertiary amines were obtained. (Melting MOIa Mo]! Per cent yield Run ras gig'a Solvent Condensing agent pH I M W ne. we

1 0.50 0.30 Alcohol 2g.sodiumaoetate... 8.81 2 0.42 0.10 .do do .s 8.81s 0.42 0.12 do do as! 4 0.30 0.13 .do (in 8.81 5 0.44 0.13 dn [in 8.81 00.40 0.13 Dionnedo 7.41 7 0.41 0.13 Alcohol... 2g.trimethylaminehydrochlorids.- 4.73 8 0.42 0.13 .do 2g.sodiumiormats 8.44 9.-...- 0.410.13 ...do 2g. sodium carbonate....... 9.22 10 0.45 0.13 --.do5cc.40%trimethylamine 9.95

Example XII.-N-di-n-butylaniline using nitrobenzene, acid conditions andplatinum catalyst points of derivatives used for identification purposesare listed in last column.)

Into the pressure bottle of a machine for catalytic reduction is placeda solution of 12.3 grams Yield Dmv'mmd (0.1 mol) of nitrobenzene, 21.6grams (0.3 mol) 01' butyraldehyde and 10 cc. of glacial acetic acid P mI in 150 cc. of 95% ethyl alcohol. To this solutionggilethylsnilinefiifin. v c 11 am 139-140 0. was then added 0.1 gram ofplatinum oxide cata- 34 d8, 1- lyst prepared according to the method ofAdams, tg l ii n i i P Plum 162-1 voorhees and Shrmer ("organicSyntheses," 1 4 N-iliniggbutylmetbyl- 50 Hdrochloride, l3l.0-l3l.5lective volume I, 1932, pa e 452) and the mixture Piu ste,86.0-87.5 c.was shaken on the machine for 96 hours during 5 gg g which time 0.66 moiof hydrogen was absorbed. a N-di-n-propylrnethyl- 4s simi n-cs 0. Afterthis hydrogenation the mixture was acidiiied with 1'1 cc. of dilutehydrochloric acid and the platinum catalyst was removed by filtration.The properties of the respective amines thus The alcohol was evaporatedfrom the filtrate, the 60 prepared were as follows:

Boiling range i a? 3 fifi'i-fl-tfitifiiit'dia: 33% 8::::::::::::: 3:???M333 3 Nflifiglyl-slphe-nsphthyililo-105 0.130 mm 1.015 1.5901

residue was then made alkaline with sodium hydroxide and extracted withether. The ether was removed from the ether extract and the product wasdistilled. The boiling range of the N-di-nbutylanillne was 265 to 275 C.and 14.5 grams of the product were obtained, which corresponds to ayield oi. 71%. based on the nitrobenzene.

Example XV.N-is0prom laniline using acetone and acid conditionsSubstituting acetone for the acetaldehyde used in Example XII inequimolecuiar amount and proceeding as otherwise therein described, asecondary amine, N-isopropylaniline, instead of a tertiary amine, wasobtained in 54% yield. The N-isopropylaniline had a boiling range of 198to 207 C. and formed a benzamide derivative having a melting point of 63to 65 C.

Example XVI.-N-isopropylmethylamine using acetone and acid conditionsAcetone and nitromethane when reacted according to the procedure ofExample XII, produced N-isopropylmethylamine in 59% yield. The producthad a boiling range of 45 to 55 C. and was identified as a picratehaving a melting point of 133 to 135 C.

Example XVIL-N-benzz/l-N-n-butylaniline usingN-benzylphenylhydroxylamine and acid condi- .tions By usingbutyraldehyde and N-benzylaniline in the molecular ratio of 2:1 andhydrogenating in accordance with the procedure described in Example XH,N-benzyl-N-n-butylaniline was obtained in 3% yield, 64% of theN-benzylaniline being recovered unchanged.

A larger and more satisfactory yield (38%) of -benzyl-N-n-butylanilinecan be obtained by reacting butyraldehyde andN-benzylphenylhydroxylamine (which can\\,be prepared by the method ofVavon and Crajq iinovic, Compt. rend., 1928, vol. 187, page 420) in themolecular ratio of 2:1 according to the procedure of Example XII, usingplatinum catalyst and acetic acid in the reaction mixture.

N-Benzyl-N-n-'-butylaniline distills at 175 to 182 C. at a pressure of10 mm., and has a specific gravity (20/20 C.) of 1.019 and a refractiveindex of 1.5810 at 20 C. for the sodium D line. Its picrate had amelting point of 126 to 128 C.

By using sodium acetate instead of acetic acid and Raney nickel catalystinstead of a platinum catalyst, as' in Example I,N-benzylphenylhydroxylamine and butyraldehyde in the molecular ratio of1:2 produced N-benzylaniline in 54% yield without the formation oi anyquantity of the tertiary amine, N-benzyl-N-n-butylaniline, that'could beisolated.

Example XVIIL-N-n-butylaniline using azobenzene and alkaline medium Intoa machine for catalytic reduction was placed a solution of 18.2 grams(0.1 mol) of ambenzene, 18.0 grams (0.25 mol) of butyraldehyde and 2grams of fused sodium acetate dissolved in 150 cc. of 95% alcohol. Tothis solution was then added about 10 grams of Raney nickel catalyst.From 2 to 40 grams of Raney nickel catalyst give satisfactory resultsbut 10 grams give a smooth and rapid reduction. Hydrogen was passed intothe mixture while the machine was shaking until 0.3 to 0.4 mol had beentaken up, the period required being approximately 1 to 2 hours. Thecatalyst was removed by filtration, the filtrate was acidified withhydrochloric acid and the alcohol was evaporated. The product wasrecovered by making the residue alkaline, extracting the alkalineresidue with ether, drying the ether extract over sodium hydroxide andsubsequently distillating the extract.

The yield of N-n-butylaniline, a secondary amine, was 71% and theproduct was identified as the p-bromobenzenesulfonamide which had amelting point or 85 to 86 C.

Example XIX.N-n-heptylaniline using aeobenzene and alkaline mediumSubstituting an equivalent amount of heptaldehyde for the butyraldehydeof Example XVIII and proceeding as therein otherwise indicated, N-n-heptylaniline was obtained in 74% yield and was identified as thep-bromobenzenesulfonamide having a melting point of 114 to 115 C.

In the case of higher molecular weight amines,

such as N-n-heptylamline, the reaction mixture after hydrogenation neednot be acidified before evaporation of the solvent (alcohol).

Example XX.-N-bene1/laniline using azobenzene and alkaline conditionsExample XXI. N-dimethyl-N'-di-n-butul-pphenylenediamine usingN-dimethyl-p-aminoazobeneene and alkaline conditions SubstitutingN-dimethyl-p-aminoazobenzene in an equivalent amount for azobenzene andproceeding as otherwise specified in Example XVIII, the products,N-dimethyl-N'-di-n-butylp-phenylenediamine in 76% yield andN-n-butylaniline in 73% yield were obtained. The picrate ofN-dimethyl-N'-di-n-butyl-p-phenylenediamine has a melting point of 121to 122 C.

The presence of the amino (or alkyl or dialkylamino) group para to theazo group has an activating influence and instead of getting solely a.secondary amine, as would be obtained under alkaline conditions with anunsubstituted azo compound, a tertiary amine is obtained. The activatinginfluence of a hydroxy group is shown in the two next examples (XXII andXXIII).

Example XXII. N-di-n-butyl-p-aminophenol using p-hydroxyazobenzene andalkaline conditions Substituting an equivalent amount ofp-hydroxyazobenzene for the azobenzene in Example XVIII and proceedingas therein otherwise indicated, the tertiary amine,N-di-n-butyl-p-aminophenol, was obtained in 46% yield. The product wasisolated as the benzoate by treating the reaction mixture with benzoylchloride and aqueous alkali.

The benzoate of N-di-n-butyl-p-aminophenol, after recrystallization fromacetic acid, has a melting point of 232 to 233 C.

Example XXIII.1 (N di n butylamino) -2- naphthol usingI-phenylaeo-Z-naphthol and alkaline conditions Utilizing the procedureof Example XVIII, by substituting l-phenylazo-Z-naphthol for azobenzenein equivalent amount, the tertiary amine 1- (N -di-n-butylamino)-2-naphthol was obtained in 41% yield. The product wa isolated by addingwater to the reaction mixture after half of the alcohol had beendistilled.

1 (N di n butylamino)-2-naphthol has a melting point of 106 to 107 C.and darkens rapidly on standing. It forms a hydrochloride that melts at225 to 227 C. and which is more stable than the free amine.

" The foregoing reactions with azo compounds may also be conducted inacid media to obtain a preponderance of tertiary'amines.

Example XXI V.'N-n-butylaniline using nitrosobenzene and alkalineconditions Utilizing the foregoing procedures, N-n-butylaniline waobtained in 45% yield by the reductive alkylation of nitrosobenzene.(0.1 mol) and butyraldehyde (0.1 mol) in the presence of Raney nickelcatalyst grams) and sodium acetate (2 grams). Aniline is alsorecoverable from the reaction mixture.

Ezample XXV.--N-benzylaniline using nitrosobenzene and alkalineconditions Using the foregoing procedures, N-benzylaniline was obtainedin 35% yield by the reductive alkylation of nitrosobenzene (0.1 mol) andbenzaldehyde (0.1 mol) in the presence of Raney nickel catalyst (5grams) and sodium acetate (2 grams). From the reaction mixture someaniline is also recoverable.

In the two foregoing examples (XXIV and XXV) the use of nitrosobenzenein the reductive alkylation required larger quantities of catalyst thanwould be required for the corresponding reduction of nitro or aminocompounds and the yields of secondary amines are lower and the productis contaminated with tars. The preparation of secondary amines fromaromatic nitroso-compounds requires a greater degree of control of thereaction than nitro or amino compounds.

The processes of the invention are applicable to the reductivealkylation of various nitrogen compounds, including aliphatic andaromatic amines such as methylamine, ethylamine, propylamines,butylamines, amylamines, aniline, ptoluidine, p-anisidine,alpha-naphthylamine, beta-naphthylamlne, phenylpropylamines(phenylaminopropanes) and the like; aliphatic and aromatic nitrocompounds such as nitromethane, nitroethane, nitropropanes,nitrobutanes, nitropentanes, nitrobenzenes, nitrotoluenes, nitrophenols,nitroanisoles, chlorinated nitrobenzenes, nitronaphthalenes,nitronaphthols, nitronaphthylamines, phenylnitropropanes and the like;aromatic nitrosoamines such as nitrosobenzene and the like; and azocompounds such as ambenzene and substituted azobenzenes such as N-dimethyl-p-aminoazobenzene, p-hydroxyazobenzene, l-phenylazo-2-naphtholand the like. The nitrogen compounds may contain chlorine, alkoxy oraryloxy substituents, for example, chloroaminobenzenes, nitroanisolcs,nitrodiphenyloxides and the like, which substituents have no substantialactivating influence. However, when amino, hydroxy or alkyl substituentsare present, as previously mentioned, the compound is activated as aresult thereof.

In the preparation of tertiary amines, N -monoalkylated secondary aminesmay be used as starting materials, as is obvious, especially when atertiary amine with two different substituents on the amino nitrogenatom is the desired product. As heretofore mentioned; the presence ofactivating groups in the nitrogen compounds particularly hydroxy, amino,and substituted amino groups, and particularly those para or ortho tothe reacting nitrogen-containing radical, influence the degree ofalkylation effected and the ease of the reaction.

Carbonyl compounds which may be used in the reaction include bothaliphatic as well as aromatic aldehyde: and ketones. Aldehydea are morereactive than ketones, as heretofore mentioned, and ketones in mostcases cannot be used to eifect alkylation beyond the formation ofsecondary amines. Examples of aldehydes and ketones which may be used inthe processes are formaldehyde, acetaldehyde, propionaldehyde,

butyraldehydes, pentaldehydes, hexaldehydes, heptaldehydes,benzaldehyde, acetone, ethyl methyl ketone, diethyl ketone,acetophenone, propiophenone and methyl Dhenyl diketone and the like.Generally branched-chain or arboraceous aldehydes and ketones do notreact as readily as straight-chain compounds. Formaldehyde, asheretofore mentioned, may lead to complications.

Although I have referred to alkylation throughout this specification, itis to be understood that the term when used in the broad sense includesthe introduction of aralkyl groups such as is effected by the use ofbenzaldehyde and the like, as well as alkyl groups. The process of theinvention,'however, finds its greatest applicability in the case ofaliphatic aldehydes whose use in such reactions has not heretofore beenpossible in a facile manner.

Although I have particularly referred to reaction mixtures containingcarbonyl compounds and nitrogen compounds as starting materials,condensation products of the two, or intermediate products of theirreductive alkylation may be used.

As hydrogenation catalysts for the reduction, Raney nickel catalysts,platinum black, palladium black and platinum oxide and similarlow-pressure hydrogenation catalysts are preferred. Catalysts such ascopper chromite are not operative at the low temperatures and pressurescontemplated by the present processes. When using acid conditions ofreaction, platinum oxide catalysts are preferred to Raney nickelcatalysts. With respect to choice of catalyst, it is also to be notedthat certain hydrogenation catalysts are more sensitive to chlorine andsulfur compounds than others and hence if the compounds involved in anyparticular reaction contain halogen or sulfur substituents, properselection of a catalyst to avoid complications should be made. Theproportion of catalyst used for the reaction may be varied over a widerange, as illustrated in certain of the examples.

The alkaline conditions referred to in this specification may beobtained by the use of sodium acetate, sodium propionate, sodiumbutyrate, sodium stearate, sodium carbonate, and

. in general, other alkali-metal salts of weak organlc acids, asdisclosed in my co-pending application Serial No. 370,355 and myapplication Serial No. 332,975. Sodium hydroxide gives a lower yield ofproduct than sodium acetate and in some cases completely suppressesalkylation, hence is to be avoided. Generally 10 grams to 20 or moregrams of fused sodium acetate should be used for each mo1 of nitrogencompound taking part in the reaction and the yields are not materiallychanged by the presence of greater proportions. Fused sodium acetate ispreferred but it is not essential that the salts used should beanhydrous.

Acid conditions referred to in this specification may be obtained by theuse of acetic acid and other weak organic acids, trimethylaminehydrochloride and similiar salts of strong (mineral) acids and weakorganic bases, containing no alkylatable hydrogen atoms attached to thenitrogen atom, preferably salts of tertiary amines. Mineral acids suchas hydrochloric acid and the aseaoov 7 like cannot be usedadvantageously. Approximately 30 to 100 grams of glacial acetic acid,for example, to each moi of reacting nitrogen compound should be used.

The reactions may be carried out in various solvents. The examplesillustrate the use of 95% ethyl alcohol and dioxane as a solvent butethyl acetate, methyl alcohol, isopropyl alcohol, isopropyl ether andthe like may be used. The essential requisite of the solvent is that itbe inert in the reaction and that it dissolve the sodium acetate,trimethylamine hydrochloride or other agent used to facilitate thereaction.

The proportion of reactants in the reaction mixture is not of paramountimportance. Generally the carbonyl compound should be in excess 01 thatrequired by the particular reaction which it is desired to eflect.

The temperatures which may be used in the reactionsvary from normal roomtemperatures to approximately 100 0., although the preferred range isabout to 40 C. Generally the reaction will proceed without the additionof extraneous heat and with large batches cooling may be desirable tocontrol the reaction. Likewise, the pressures may be varied greatly, forexample, from normal atmospheric pressure to 10 or more atmospheres.Preferred pressure conditions, however, are from 2 to 4 atmospheres.

By interrupting the reductive alkylation of aromatic nitrocompounds withaliphatic or aromatic aldehydes according to the present invention at anintermediate stage it is possible to isolate substantial amounts ofhydroxylamines. The media may be either acid or alkaline as hereindescribed. These hydroxylamines can be rearranged with acids such assulfuric acid to give the corresponding aminophenols. Hence, by thisprocedure I am able to produce substituted bydroxylamines andaminophenols in an advantageous manner. Furthermore, these intermediateproducts indicate the probable mechanism of reductive alkylationprocesses according to the invention. Briefly the reactions may betypified by that of nitrobenzene and an aldehyde (RCHO) which may berepresented as follows: i

H: RCHO G G 1? N-cmR H: cum

N-benzylphenylhydroxylamine prepared by interrupting the reductivealkylation of nitrobenzene with benzaldehyde, condenses withn-butyraldeweak organic acid" is to be understood to sig- 7 nifymonocarboxylic aliphatic acids such as acetic acid, formic acid.propionic acid, butyric acid, dicarboxylic and polycarboxylic acids andthe like and to distinguish from strong organic acids such asbenzenesulfonic acids and similar non-cab.

5 boxylic acids and mineral acids.

Inasmuch as the foregoing description comprises preferred embodiments ofthe invention. it is to be understood that my invention is not to belimited thereto and that modifications and 1 variations may be madetherein to adapt the invention to'other specific uses without departingsubstantially from its spirit or scope as defined in the appendedclaims;

I claim:

1s 1. The process of producing an N-alkylated aromatic amines, aliphaticand aromatic nitro compounds and aromatic nitroso and azo compounds, andthe other or which is an aldehyde in the presence of a hydrogenationcatalyst and a condensing agent consisting of a. salt of a mineral acidand an organic base.

2. In the method of producing an- N-alkylated organic compound by thehydrogenation in the presence of a hydrogenation catalyst of a mixtureof two compounds, one of which is an organic nitrogen compound free fromhydroxyl and amino substituents and selected from the group consistingof primary and secondaryaliphatic and aromatic amines, aliphatic andaromatic nitro compounds and aromatic nitroso and azo compounds, and theother of which is an aidehyde, the improvement comprising conducting thehydrogenation in the presence of a condensing agent consisting of a saltof a mineral acid and an organic base.

3. The process as defined in claim 1 in which the condensing agent istrimethylamine hydrochloride.

4. The process as defined in claim 1 in which the hydrogenation catalystis of the Honey nickel type '5. The process of producingN-di-n-butylaniline comprising the hydrogenation of a mixture ofbutyraldehyde and nitrobenzene in the presence of a Raney nickelcatalyst and trimethylamine hydrochloride at a temperature withintherange of approximately 15? to 100 C. and at a pressure of approximately1 to 4 atmospheres.

6. The process of producing an N-butylated aromatic amine comprising thehydrogenation of a mixture of an aromatic nitro compound and abutyraldehyde in the presence of a hydrogenation catalyst and acondensing agent consisting of trimethylamine hydrochloride.

7. The process of producing an N-alkylated aromatic amine comprising thehydrogenation of a mixture of an aromatic nitro compound and analiphatic aldehyde in the presence of a hydrogenation catalyst and acondensing agent consisting oi a salt of a mineral acid and an organicbase ' 8. The process as defined in claim I and further characterized inthat the condensing agent is trimethylamine hydrochloride. 0

WILLIAM S. EMERSON.

vCERTIFICA'I'E 0F CORIEC'IION. Patent No. 2,388,6 7 November 6, 915.

WILLIAM S; EMERSON.

It is hereby certified. that error appeare in the printed specificationof the above numbered patent requiring correction as follows: Page 14.,Exam-' ple X1, in the table, third column thereof, for "9.12'! read --O.12.--; and

that the said Letters Patent should be read. with this correctiontherein that the same may conform to the record. of the case in thePatent Office.

Signed and. sealed this th day of February, A. D. 191 .6.

L'es lierF razer (Seal) First Assistant Commissioner or Patehts.

